Certain isoquinoline derivatives having anti-tumor properties

ABSTRACT

Compounds are described of general formula (I) ##STR1## and salts and solvates thereof, including physiologically acceptable salts and solvates thereof, in which: 
     Z represents either Het, ##STR2## Het represents an optionally substituted bicyclic or tricyclic ring selected from acricine isoquinolin-1-yl, isoquinolin-3-yl, 
     The novel compounds of formula (I) can sensitize multi-drug resistant cancer cells to chemotherapeutic agents and may be formulated for use in therapy, particularly to improve or increase the efficacy of an anti-tumour drug.

CROSS REFERENCE

This application is a 371 of PCT/EP93/01802 filed 07/08/93

This is invention relates to anilide derivatives, to processes for theirpreparation, to pharmaceutical compositions containing them, and totheir medical use. In particular it relates to compounds andcompositions which are capable of sensitizing multidrug-resistant cancercells to chemotherapeutic agents.

In many patients, the efficacy of cancer chemotherapy is initially pooror decreases after initial treatment due to the development ofresistance to anticancer drugs, known as multidrug-resistance.Multidrug-resistance is a process whereby malignant cells becomeresistant to structurally diverse chemotherapeutic agents followingtreatment with a single anti-tumour drug. This acquired drug resistancecan be a major clinical obstacle in the treatment of cancer. Sometumours are intrinsically multidrug-resistant, and hence do not respondto chemotherapy.

It has been shown that this type of resistance can be reversed by somecalcium channel blockers such as nicardipine and verapamil, byantiarrhythmic agents such as amiodarone and quinidine, as well as bynatural products such as cepharanthine. However, these compounds exerttheir multidrug resistant cell sensitizing activity only at very highdoses, well above their intrinsic toxic level, and this severely limitstheir clinical use in the field of cancer chemotherapy.

A novel group of compounds has now been found which can sensitizemultidrug-resistant cancer cells to chemotherapeutic agents at doselevels at which these novel compounds show no toxicity.

Thus, the present invention provides a compound of formula (I): ##STR3##and salts and solvates thereof, including physiologically acceptablesalts and solvates thereof, in which:

A represents an oxygen or a sulphur atom, a bond or a group (CH₂)_(l)NR⁷ (where l represents zero or 1 and R⁷ represents a hydrogen atom or amethyl group);

B represents a C₁₋₄ alkylene chain optionally substituted by a hydroxylgroup, except that the hydroxyl group and moiety A cannot be attached tothe same carbon atom when A represents an oxygen or sulphur atom or agroup (CH₂)_(l) NR⁷, or when A represents a bond B may also represent aC₂₋₄ alkenylene chain;

R¹ represents a hydrogen atom or a C₁₋₄ alkyl group;

m represents 1 or 2;

R² represents a hydrogen or a halogen atom, or a C₁₋₄ alkyl, C₁₋₄ alkoxyor C₁₋₄ alkylthio group;

R³ represents a hydrogen atom or a C₁₋₄ alkoxy group;

R⁴ represents a hydrogen atom or a C₁₋₄ alkyl or C₁₋₄ alkoxy group;

R⁵ represents a hydrogen atom or R¹ and R⁵ together form a group--(CH₂)_(n) -- where n represents 1 or 2;

R⁶ represents a hydrogen atom or a C₁₋₄ alkoxy group; the group ##STR4##is attached at the benzene ring 3 or 4 position relative to thecarboxamide substituent, provided that when the group is attached at thebenzene ring 3 position then R⁴ must be attached at the benzene ring 6position; and

Z represents either Het, ##STR5## Het represents an optionallysubstituted bicyclic or tricyclic ring selected from quinolin-4-yl,isoquinolin-1-yl, isoquinolin-3-yl, quinolin-3-yl, quinolin-2-yl,quinoxalin-2-yl, naphthalen-1-yl, naphthalen-2-yl, indol-2-yl,4-oxo-4H-1-benzopyran-2-yl, phenazin-1-yl and phenothiazin-1-yl or anaryl substituted monocyclic ring selected from 2-aryl-4-thiazolyl,2-aryl-5-thiazolyl, 5-aryl-2-thienyl, 2-aryl-4-triazolyl and1-aryl-4-pyrazolyl where aryl represents a phenyl or pyridyl ringoptionally substituted by a halogen atom or a trifluoromethyl, C₁₋₄alkyl or C₁₋₄ alkoxy group. The above mentioned bicyclic or tricyclicrings may be unsubstituted or substituted by one, two or three groupsselected from C₁₋₄ alkyl and C₁₋₄ alkoxy. Quinolin-4-yl rings may alsobe substituted in the ring 2 position by phenyl or phenyl substituted byC₁₋₄ alkoxy. Indol-2-yl rings may also be substituted in the ring 3position by benzoyl;

R⁸ represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₄ alkylthio, amino or nitro group;

p represents 1; or when R⁸ represents C₁₋₄ alkoxy p may also represent 2or 3;

R⁹ represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy orC₁₋₄ alkylthio group;

R¹⁰ and R¹¹ may each represent a hydrogen atom or together form a bondor a linking atom selected from --O-- or --S--; and

X represents an oxygen atom or NR¹² (where R¹² represents a hydrogenatom or a C₁₋₄ alkyl group).

As used herein, an alkyl group, either as such or as part of an alkoxyor alkylthio group may be a straight chain or branched chain alkylgroup, for example a methyl, ethyl or prop-2-yl group.

A halogen substituent may be a fluorine, chlorine, bromine or iodineatom.

The groups represented by R⁸ and R⁹ may be situated at any availablepositions in the relevant benzene rings.

Examples of the chain --A--B--CH₂ -- include --(CH₂)₂ --, --(CH₂)₃ --,--(CH₂)₄ --, --(CH₂)₅ --, --CH₂ NMe(CH₂)₂ --, --CH═CHCH₂ --, --CH₂CH═CHCH₂ --, --CH(OH)CH₂ --, --O(CH₂)₂ --, --O(CH₂)₃ --, --OCH₂CH(OH)CH₂ --, --NH(CH₂)₂ --, --S(CH₂)₂ -- and --S(CH₂)₃ --.

When R¹ represents a hydrogen atom or a C₁₋₄ alkyl group, preferably R¹represents a C₁₋₄ alkyl (e.g. methyl) group.

R⁸ preferably represents a hydrogen or fluorine atom or a C₁₋₄ alkoxy(e.g. methoxy), C₁₋₄ alkyl (e.g. methyl) or C₁₋₄ alkythio (e.g.methylthio) group.

R⁹ preferably represents a hydrogen atom or a C₁₋₄ alkoxy (e.g. methoxy)group.

A preferred class of compounds of formula (I) is that in which R²represents a hydrogen atom or a C₁₋₄ alkoxy (e.g. methoxy) group, R³represents a hydrogen atom or a C₁₋₄ alkoxy (e.g. methoxy) group and R⁶represents a hydrogen atom or a C₁₋₄ alkoxy (e.g methoxy) group,provided that at least one of R², R³ and R⁶ represents a C₁₋₄ alkoxy(e.g. methoxy) group. A particularly preferred class of compounds offormula (I) is that in which R² and R³ each represent a C₁₋₄ alkoxy(e.g. methoxy) group and R⁶ represents a hydrogen atom.

R⁴ preferably represents a hydrogen atom or a methyl, ethyl, methoxy orethoxy group. Compounds of formula (I) in which R⁴ represents a hydrogenatom are particularly preferred.

A preferred group of compounds of formula (I) is that in which mrepresents 1 and R¹ and R⁵ together form a group --(CH₂)₂ --, andphysiologically acceptable salts and solvates thereof.

A particular group of compounds of formula (I) is that of formula (Ia)##STR6## wherein Z is as defined in formula (I) above; A represents anoxygen or a sulphur atom or a bond;

B represents an unsubstituted C₁₋₄ alkylene chain;

R² and R³ each independently represents a C₁₋₄ alkoxy group; (egmethoxy); and physiologically acceptable salts and solvates thereof.

A particular group of compounds of Formula (Ia) are compounds in which Zrepresents Het as previously defined.

Another particular group of compounds of Formula (Ia) are compounds inwhich Z represents ##STR7## wherein R⁸ represents a hydrogen or halogenatom or a C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio or nitro group, R⁹represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy orC₁₋₄ alkylthio group and R¹⁰ and R¹¹ are as previously defined.

A further particular group of compounds of formula (Ia) are compounds inwhich Z represents ##STR8## wherein R⁸ represents a hydrogen or halogenatom or a C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio or nitro group, R⁹represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy orC₁₋₄ alkylthio group and X represents an oxygen atom or NH.

Particularly preferred compounds of formula (Ia) are those in which R⁸represents a hydrogen or fluorine atom or a C₁₋₄ alkoxy (e.g. methoxy)or C₁₋₄ alkyl (e.g. methyl) group and R⁹ represents a hydrogen atom.

It is to be understood that the present invention includes allcombinations of the aforementioned particular and preferred groups.

Suitable physiologically acceptable salts of the compounds of formula(I) include acid addition salts formed with organic or inorganic acids,for example, hydrochlorides, hydrobromides, sulphates, alkyl- orarylsulphonates (e.g. methanesulphonates or p-toluenesulphonates),phosphates, acetates, citrates, succinates, lactates, tartrates,fumarates and maleates. The solvates may, for example, be hydrates.

Other salts which are not physiologically acceptable may be useful inthe preparation of compounds of formula (I) and these form a furtherpart of the invention.

The ability of the compounds of formula (I) to sensitizemultidrug-resistant cells has been demonstrated in vitro in themultidrug-resistant Chinese hamster ovary cell line (described byBech-Hansen et al., J. Cell. Physiol., 1976, 88.23-32) and themultidrug-resistant human mammary carcinoma line (described by Batist etal., (J. Biol. Chem., 1986, 261, 1544-1549) using an assay similar tothat described by Carmichael et al., Cancer Research, 1987, 47, 936.

The ability of the compounds of formula (I) to sensitizemultidrug-resistant cells has also been demonstrated in vivo in thetumour line P388R (described by Johnson et al., Cancer Treat. Rep.,1978, 62, 1535-1547). The methodology used is similar to that describedby Boesch et al., Cancer Research, 1991, 51, 4226-4233. However, in ourstudy the compounds were administered orally, intravenously orintraperitoneally in a single dose.

The present invention accordingly provides a compound of formula (I) ora physiologically acceptable salt or solvate thereof for use in therapy,more particularly for use in the treatment of a mammal, including ahuman, which is suffering from cancer to:

(a) improve or increase the efficacy of an antitumour drug; or

(b) increase or restore sensitivity of a tumour to an antitumour drug;or

(c) reverse or reduce resistance, whether acquired, induced or inate, ofa tumour to an antitumour drug.

The present invention also provides a method of treatment of a mammal,including a human, which is suffering from cancer, which methodcomprises administering to said mammal an effective amount of a compoundof formula (I) or a physiologically acceptable salt or solvate thereofto:

(a) improve or increase the efficacy of an antitumour drug; or

(b) increase or restore sensitivity of a tumour to an antitumour drug;or

(c) reverse or reduce resistance, whether acquired, induced or inate, ofa tumour to an antitumour drug.

In another aspect, the present invention provides the use of a compoundof formula (I) or a physiologically acceptable salt or solvate thereoffor the manufacture of a medicament for the treatment of a mammal,including a human, which is suffering from cancer to:

(a) improve or increase the efficacy of an antitumour drug; or

(b) increase or restore sensitivity of a tumour to an antitumour drug;or

(c) reverse or reduce resistance, whether acquired, induced or inate, ofa tumour to an antitumour drug.

It will be appreciated that the compounds according to the presentinvention are administered in conjunction with an antitumour drug. Thus,in a further aspect, the present invention provides a product containinga compound of formula (I) or a physiologically acceptable salt orsolvate thereof and an antitumour drug as a combined preparation forsimultaneous, separate or sequential use in treating cancer, moreparticularly to:

(a) improve or increase the efficacy of said antitumour drug; or

(b) increase or restore sensitivity of a tumour to an antitumour drug;or

(c) reverse or reduce resistance, whether acquired, induced or inate, ofa tumour to an antitumour drug.

Examples of suitable antitumour drugs for use in conjunction withcompounds of the present invention include Vinca alkaloids (e.g.vincristine, vinblastine and vinorelbine), anthracyclines (e.g.daunorubicin, doxorubicin and aclarubicin), taxol and derivativesthereof (e.g. taxotere), podophyllotoxins (e.g. etoposide and VP16),mitoxantrone, actinomycin, colchicine, gramicidine D, amsacrine or anydrug having cross-resistance with the above drugs characterised by theso-called MDR phenotype.

It will be appreciated that if administration of the two drugs is notsimultaneous, the delay in administering the second of the activeingredients should not be such as to lose the beneficial effect of thecombination,

Thus, in a further aspect, the present invention provides a compound offormula (I) or a physiologically acceptable salt or solvate thereof andan anticancer drug in the presence of each other in the human ornon-human animal body for use in treating cancer, more particularly to:

(a) improve or increase the efficacy of said antitumour drug; or

(b) increase or restore sensitivity of a tumour to an antitumour drug;or

(c) reverse or reduce resistance, whether acquired, induced or inate, ofa tumour to an antitumour drug.

Some tumours are often intrinsically multidrug-resistant, notably coloncarcinomas, renal cell carcinomas, hepatomas and adrenocorticalcarcinomas.

Other types of tumour are often initially sensitive but can becomemultidrug-resistant, notably leukaemias, lymphomas, myelomas, paediatrictumours (e.g. neuroblastomas), sarcomas, and breast, ovarian and lungcancers.

Hence the compounds of the invention are particularly useful in thetreatment of mammals, including humans, receiving chemotherapy for oneof the above types of cancer.

In using a compound of formula (I) or a physiologically acceptable saltor solvate thereof and an antitumour drug it may be preferable to employthe active ingredients in the form of separate pharmaceuticalformulations, although a single combined formulation can be used asdemonstrated hereinafter. However, in the latter formulation both activeingredients must of course be stable and mutually compatible in theparticular formulation employed.

Pharmaceutical formulations of suitable antitumour drugs and appropriatedosages and dosage rates will generally correspond with those one woulduse if administering the antitumour drug alone to treat a tumour.

Suitable pharmaceutical formulations and appropriate dosages and dosagerates of compounds of formula (I) and physiologically acceptable saltsand solvates thereof are described hereinafter.

Thus, in a further aspect, the invention provides a pharmaceuticalcomposition which comprises a compound of formula (I) or aphysiologically acceptable salt or solvate thereof together with one ormore physiologically acceptable carriers or excipients.

In another aspect, the present invention provides a pharmaceuticalcomposition which comprises an active amount of a compound of formula(I) or a physiologically acceptable salt or solvate thereof for use inthe treatment of a mammal which is suffering from cancer, to:

(a) improve or increase the efficacy of an antitumour drug; or

b) increase or restore sensitivity of a tumour to an antitumour drug; or

(c) reverse or reduce resistance, whether acquired, induced or inate, ofa tumour to an antitumour drug.

The compounds according to the invention may be formulated for oral,buccal, parenteral or rectal administration, of which oral andparenteral are preferred.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. sodium lauryl sulphate or sodium starchglycolate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily,aqueous or alcoholic vehicles, and may contain formulatory agents suchas suspending, stabilising and/or dispersing agents. Alternatively, theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

A proposed daily dose of the compounds of the invention foradministration to a human (of approximately 70 kg body weight) is about10 mg to 1000 mg, more preferably about 25 mg to 500 mg. It will beappreciated that it may be necessary to make routine variations to thedosage, depending on the age and condition of the patient, and the routeof administration. For example, a daily dose of about 1 mg/kg may beappropriate for administration to a human by infusion. The daily dosemay be given as a single unit or as two or more subunits administeredafter appropriate time intervals.

Compounds of general formula (I) and physiologically acceptable saltsand solvates thereof may be prepared by the general methods outlinedhereinafter. In the following description, the groups Z, R¹ to R⁶, m, Aand B are as defined for compounds of formula (I) unless otherwisespecified.

Thus according to a first general process (A), a compound of formula (I)may be prepared by reacting a compound of formula (II):

    Z--CO.sub.2 H                                              (II)

with a compound of formula (III) ##STR9##

The reaction may be effected using a coupling reagent standardly used inpeptide synthesis, such as dicyclohexylcarbodiimide (optionally in thepresence of 1-hydroxybenzotriazole), diphenylphosphoryl azide orN,N'-carbonyldiimidazole. The reaction may be conveniently effected inan inert solvent such as an ether (e.g. tetrahydrofuran), a halogenatedhydrocarbon (e.g. dichloromethane), an amide (e.g. dimethylformamide) ora ketone (e.g. acetone), and at a temperature of, for example, -10° to+100° C., more preferably at about room temperature.

According to another general process (B), a compound of formula (I) maybe prepared by reacting a compound of formula (IV): ##STR10## wherein Qrepresents a halogen (e.g. bromine) atom, with a compound of formula(V): ##STR11## or a salt thereof. The reaction may be effected in thepresence of an acid acceptor such as an alkali metal carbonate (e.g.potassium carbonate), in the presence or absence of a solvent, at anelevated temperature (e.g. 50° to 120° C.). Suitable solvents includeketones (e.g. acetone, methylethylketone or methylisopropylketone) andalcohols (e.g. ethanol or isopropanol).

Compounds of formula (III) may be prepared according to the methodologydescribed in published European Application 0494623.

Compounds of formula (IV) may be prepared by the reaction of a compoundof formula (II) as defined previously, with a compound of formula (VI):##STR12## wherein Q represents a halogen (e.g. bromine) atom, under theconditions described in process (A) above for the reaction of a compoundof formula (II) with a compound of formula (III).

Intermediates of formula (IV) are novel compounds and represent afurther aspect of the present invention.

Compounds of formula (II) are either known in the art or may be preparedby conventional methods, for example as described in the Examplessection hereinafter.

Compounds of formulae (V) and (VI) are either known in the art or may beprepared according to the methodology described in published EuropeanApplication 0494623.

Where it is desired to isolate a compound of the invention as a salt,for example a physiologically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate acid, preferably with an equivalent amount, in a suitablesolvent such as an alcohol (e.g. ethanol or methanol), an aqueousalcohol (e.g. aqueous ethanol), a halogenated hydrocarbon (e.g.dichloromethane), an ester (e.g. ethyl acetate) or an ether (e.g.tetrahydrofuran), or a mixture of two or more of such solvents.

Physiologically acceptable salts may also be prepared from other salts,including other physiologically acceptable salts, of the compound offormula (I) using conventional methods.

The invention is further illustrated by the following Intermediates andExamples which are not intended to limit the invention in any way. Alltemperatures are in °C. ¹ H NMR spectra were obtained for dilutesolutions in CDCl₃ unless otherwise stated. Solvents were dried, whereindicated, over sodium sulphate. Silica gel used for columnchromatography was Merck 60, 230-400 mesh. The following abbreviatonsare used: THF--tetrahydrofuran; DMF--dimethylformamide.

INTERMEDIATE 1

Ethyl 3,4-dihydro-6-methoxy-3-oxo-2-quinoxalinecarboxylate2-amino-4-methoxyaniline (25 g) triethylamine (25.4 ml) and ethanol (250ml) were stirred under nitrogen at 5°. Diethyl bromomalonate (40.1 ml)in ethanol (50 ml) was added dropwise over 30 min. The mixture wasstirred at 5° for 30 minutes. After 16 hours at room temperature, theprecipitate was filtered off and stirred in water (800 ml) containing 1Nhydrochloric acid (100 ml) for 1 hour. The mixture was filtered. Theresidue was washed with water and dried in vacuo to give the titlecompound (15.3 g) as a solid, mp: 227°.

INTERMEDIATE 2

(a) Ethyl 3-chloro-6-methoxy-2-quinoxalinecarboxylate

Phosphorous oxychloride (46 ml) was added to Intermediate 1 (10 g). Themixture was heated at 100° for one hour, allowed to cool, and thencarefully poured into ice (800 g). The pH of this mixture was adjustedto 3 by addition of aqueous ammonia. The resulting yellow solid wasfiltered off, washed with water, and recrystallised from aqueous acetoneto give the title compound (10.08 g) as a solid, mp=75°.

The following compound was prepared in a similar manner:

(b) Ethyl 3-chloro-6,7-dimethyl-2-quinolaxinecarboxylate

The title compound (10.7 g) was obtained as a solid, mp=115° from ethyl3,4-dihydro-3-oxo-6,7-dimethyl-2-quinoxalinecarboxylate* (10 g).

INTERMEDIATE 3

(a) 3-Methoxy-6,7-dimethyl-2-quinoxalinecarboxylic acid

Intermediate 2(b) (2 g) was added to a solution of sodium (0.43 g) indry methanol (100 ml). The solution was refluxed for 1 hour, cooled toroom temperature and water (20 ml) was added. The solution was refluxedfor 1 hour. The cool solution was filtered off. The filtrate wasacidified to pH 3 with 2N hydrochloric acid. The product crystallisedand was then filtered, washed with water and dried in vacuo to give thetitle compound (1.59 g) as a solid, mp=180°-182°.

The following compound was prepared in a similar manner:

(b) 3-Ethoxy-6,7-dimethyl-2-quinoxalinecarboxylic acid

The title compound (0.88 g) was obtained as a solid, mp=116°, fromIntermediate 2(b) (1.3 g) in ethanol.

INTERMEDIATE 4

Ethyl 6-methoxy-3-ethylthio-2-quinoxalinecarboxylate

To a suspension of sodium hydride (1.8 g) in THF was added a solution ofethanethiol in dry THF (30 ml). After 15 min, a solution of Intermediate2(a) (10 g) in dry THF (50 ml) was added. The mixture was stirred atroom temperature for 16 hours. The precipitate was filtered off and thefiltrate was evaporated. The residue was extracted with dichloromethane,washed with water, dried, concentrated in vacuo and recrystallised fromisopropanol (50 ml), to give the title compound (5 g) as a solid,mp=70°.

INTERMEDIATE 5

Ethyl 6-methoxy-2-quinoxalinecarboxylate

To a solution of Intermediate 4 (5 g) was carefully added Raney nickel(80 g). The mixture was stirred at room temperature for 1 hour. TheRaney nickel was filtered off and the filtrate was concentrated invacuo. The residue was purified by flash chromatography on silica geleluting with cyclohexane:ethylacetate (70:30) to give the title compound(2.5 g) as a solid.

NMR includes δ1.48 (3H,t,CH₃); 3.84(3H,s,OCH₃); 4.57(2H,q,CH₂).

INTERMEDIATE 6

6-Methoxy-2-quinoxalinecarboxylic acid

To a solution of Intermediate 5 (2.5 g) in ethanol (60 ml) was added anaqueous solution of 30% sodium hydroxide. The mixture was refluxed for30 minutes. After evaporation, the mixture was acidified by addition of1N hydrochloric acid. The white crystals were filtered off and dried togive the title compound (2 g) as a solid, mp=248°.

INTERMEDIATE 7

2-Methoxy-3'-methylbenzophenone

A mixture of 2-methoxybenzonitrile (4.3 ml) and the Grignard reagent ofm-bromotoluene (6.6 g) in ether was refluxed for 1 h and hydrolysed withdilute hydrochloric acid with heating. The aqueous layer was thenextracted with ether, and the resultant organic layer was dried andevaporated to give the title compound (5.5 g) as an oil.

INTERMEDIATE 8

3-(2-Methoxybenzoyl)benzoic acid

A solution of Intermediate 7 (5.4 g) in a mixture of pyridine (50 ml)and water (70 ml) was heated to 50° and treated dropwise with potassiumpermanganate (19 g). The mixture was then refluxed for 2 h, cooled toroom temperature, filtered and the salts were washed with hot water. Theaqueous solution was then acidified with sulphuric acid and extractedwith dichloromethane. The organic layer was then dried and evaporated togive the title compound (4.4 g) as a solid, mp=170°-172°.

INTERMEDIATE 9

(a) 1-(3-Bromopropoxy)-3-methoxy-4-nitrobenzene

A mixture of 3-methoxy-4-nitrophenol (Intermediate 18 in EP-A-494623)(2.4 g), 1,3-dibromopropane (7.5 ml) and potassium carbonate (2.2 g) inDMF (30 ml) was stirred at room temperature for 24 h. The mixture wasfiltered and the filtrate was evaporated to dryness. The residue wastreated with water and extracted with dichloromethane. The organicextract was then washed with 5% sodium hydroxide solution and brine,dried and concentrated in vacuo to give the title compound (3.5 g) as anoil.

NMR includes δ2.3 (2H,m,CH₂), 3.6 (2H,t,CH₂ Br), 3.8 (3H,s,OCH₃), 4.1(2H,t, CH₂ O).

The following compounds were prepared in a similar manner toIntermediate 9(a):

(b) 1-(4-Bromobutoxy)-4-nitrobenzene

The title compound was obtained from 4-nitrophenol and1,4-dibromobutane.

NMR includes δ4.01 (2H,m,CH₂ Br), 3.4 (2H,m,CH₂ Ar).

(c) 1-(3-Bromopropoxy)-3-methyl-4-nitrobenzene

The title compound (33 g) was obtained as an oil from3-methyl-4-nitrophenol (25 g) and 1,3-dibromopropane (83 ml).

NMR includes δ2.3 (2H,m,CH₂), 2.5 (3H,s, CH₃), 3.6 (2H,t,CH₂ Br), 4.1(2H,t, OCH₂).

INTERMEDIATE 10

(a)1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[3-(3-methoxy-4-nitrophenoxy)propyl]isoquinoline

A mixture of Intermediate 9(a) (0.7 g),1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline (0.4 g) and potassiumcarbonate (0.36 g) in DMF (25 ml) was heated at 60° for 16 h. Themixture was filtered and the filtrate was evaporated. The residue wastreated with water and extracted with dichloromethane. The organic layerwas dried, concentrated, and the resultant residue was purified bycolumn chromatography eluting with dichloromethane:methanol (99:1) togive the title compound (0.64 g) as an oil.

NMR includes δ3.8 (9H,2s, 3×OCH₃).

The following compounds were prepared in a similar manner toIntermediate 10(a):

(b)1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[4-(4-nitrophenoxy)butyl]isoquinoline

The title compound was obtained from Intermediate 9(b) and1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline.

NMR includes δ3.7(2H,s,NCH₂ Ar), 3.9(2H,t,OCH₂).

(c) 1,2,3,4-Tetrahydro-6,7-dimethoxy-2-[3-(3-methyl-4-nitrophenoxy)propyl]isoquinoline

The title compound (5.3 g) was obtained as an oil from Intermediate 9(c)(5.7 g) and 1,2,3,4- tetrahydro-6,7-dimethoxyisoquinoline (4.0 g).

NMR includes δ2.5 (3H,s,CH₃), 3.8 (6H,s, 2×OCH₃)

(d) N-Methyl-N-(4-nitrobenzyl)veratrylamine

The title compound was obtained as an orange oil from4-nitrobenzylbromide and N-methylveratrylamine.

NMR includes δ3.8 (6H, s, 2×OCH₃), 2.2 (3H, s, NCH₃), 3.65 (2H, s, NCH₂C₆ H₁ NO₂₋ p), 3.5(2H, s, NCH₂ C₆ H₃ (OCH₃)₂).

(e) N-Methyl-N-[3-(4-nitrophenoxy)propyl]benzylamine

The title compound was obtained as the hydrochloride salt (from diethylether) from 1-(3-bromopropoxy)-4-nitrobenzene and N-methylbenzylamine.mp=170°-172°.

INTERMEDIATE 11

(a)2-Methoxy-4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine

A solution of Intermediate 10(a) (0.64 g) in ethanol (25 ml) washydrogenated at room temperature and atmospheric pressure in thepresence of 10% palladium on carbon (60 mg). After hydrogen absorptionwas completed, the catalyst was filtered off and the solution wasconcentrated in vacuo to give the title compound (0.4 g) as a solid.

NMR includes δ3.8 (9H,s, 3×OCH₃), 3.0 (2H,bs,NH₂).

The following compounds were prepared in a similar manner toIntermediate 11(a):

(b)4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-isoquinolinyl)butoxy]benzenamine

The title compound was obtained from Intermediate 10(b), mp=114°.

(c) 2-Methyl-4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine

The title compound (4.8 g) was obtained as an oil (which subsequentlycrystallised) from Intermediate 10(c) (5.3 g).

NMR includes δ2.1 (3H,s,CH₃), 3.8 (6H,s, 2×OCH₃).

(d) N-(4-Aminobenzyl)-N-methylveratrylamine

The title compound was obtained as a yellow oil from Intermediate 10(d).

NMR includes δ3.75 (s, 6H 2×OCH₃), 3.5(4H, 2×NCH₂ Ph), 2.1(3H, s, NCH₃).

(e) 4-[3-(N-methylbenzylamino)propoxyaniline

The title compound was obtained as an oil from Intermediate 10(e). NMRincludes δ3.9 (t, 2H, O--CH₂), 3.4(s, 2H, CH₂ Ph), 2.1(t, 2H, N--CH₂),2.0(s, 3H, N--CH₃), 1.85(m, 2H, CH₂).

INTERMEDIATE 12

1-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-3-(4-nitrophenoxy)-2-propanol

A mixture of 1,2-epoxy-3-(4-nitrophenoxy)propane (4 g) and6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5.4 g) in isopropanol (100ml) was heated under reflux for 3 h and evaporated. The residue waspurified by column chromatography to give the title compound (7.6 g) asa yellow oil which solidified on standing.

INTERMEDIATE 13

1-(4-Aminophenoxy)-3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-2-propanol

A solution of Intermediate 12 (4 g) in ethanol (1 00 ml) washydrogenated at room temperature in the presence of 10% palladium oncarbon (0.4 g). After the hydrogen absorption was completed, thecatalyst was filtered off and the filtrate concentrated in vacuo to givethe title compound (3.5 g) as an off white solid, mp=106°.

INTERMEDIATE 14

3-(3-Methoxybenzoyl)benzoic acid

A solution of 3-methoxy-3'-methylbenzophenone* (8 g) in a mixture ofpyridine (50 ml) and water (100 ml) was heated to 50° and treateddropwise with potassium permanganate (22 g). The mixture was thenrefluxed for 12 h, cooled to room temperature, filtered and the saltswashed with hot water. The aqueous solution was then acidified withsulphuric acid and the resultant solid was filtered off andrecrystallised from a mixture of ethanol/water to give the titlecompound (5.8 g) as a solid, mp: 160°.

INTERMEDIATE 15

3-(4-Fluorobenzoyl)benzoic acid

A suspension of 4'-fluoro-3-methylbenzophenone* (1.8 g) in water (70 ml)was treated dropwise with potassium permanganate (5.3 g) and the mixturewas refluxed for 12 h. After cooling to room temperature, the salts werefiltered and washed with hot water. The aqueous solution was thenacidified with concentrated hydrochloric acid and the resultant solidwas filtered off and dried to give the title compound (1.2 g) as asolid, mp: 180°.

INTERMEDIATE 16

Methyl 5-(3-fluorobenzoyl)-2-methoxybenzoate

Aluminium trichloride (16.2 g) and 3-fluorobenzoyl chloride (7.5 ml)were added to 1,2-dichloroethane (120 ml) at room temperature. Themixture was cooled to -5° and salicylic acid (8.3 g) was addedportionwise and the mixture was heated to 40°. After 12 h at 40°, themixture was cooled, poured into ice and acidified with 2N hydrochloricacid. Extraction with ethyl acetate and evaporation gave a white solid.A portion (10 g) of the solid was dissolved in dimethylsulphoxide (60ml) and potassium carbonate (16 g) was added. After 1 h at roomtemperature, iodomethane (9.6 ml) was added and the mixture was heatedat 40° for 3 h. After cooling, the mixture was poured in to ice and theprecipitate was purified by chromatogaphy eluting with toluene/ethylacetate (90/10) to give the title compound (7 g) as a solid, mp: 140°.

INTERMEDIATE 17

N-Benzyl-N-methyl-2-(4-nitrophenoxy)acetamide

MP 95°-96°. Prepared from (4-nitrophenoxy) acetic acid andN-methylbenzylamine according to the method used in Intermediate 34(a)in EP-A-494623.

INTERMEDIATE 18

N-Benzyl-N-methyl-2-(4-aminophenoxy)acetamide as an oil.

NMR includes signals at δ4.8(s, 2H, O--CH₂ --CO.sub.), 3.7(s, 2H, CH₂Ph), 2.8(s, 3H, N--CH₃). Prepared from Intermediate 17 according to themethod used in Intermediate 35(a) in EP-A-494623.

INTERMEDIATE 19

4-[2-(N-Methylbenzylamino)ethoxy]aniline as a red oil. NMR includessignals at δ3.9(t, 2H, O--CH₂), 3.5(s, 2H, CH₂ --Ph), 2.1(t, 2H,N--CH₂), 2.0(s,3H, N--CH₃). Prepared from Intermediate 18 according tothe method used in Intermediate 36(a) in EP-A-494623.

INTERMEDIATE 20

5-(3-Fluorobenzoyl)-2-methoxybenzoic acid

To a suspension of Intermediate 16 (4.3 g) in water (50 ml) was addedpotassium hydroxide (2.5 g) and the mixture was heated at reflux for 2h. After cooling, the solution was acidified with 1N hydrochloric acidand the white precipitate was filtered off and dried to give the titlecompound (4 g) as a solid, mp: 200°.

INTERMEDIATE 21

Methyl 5-benzoyl-2-methoxybenzoate

Aluminium trichloride (16.2 g) and benzoyl chloride (7 ml) were added to1,2-dichloroethane (100 ml) at room temperature. The mixture was cooledto -5° and salicylic acid (8.3 g) was added portionwise and the mixturewas heated to 60°. After 12 h at 60°, the mixture was cooled, pouredinto ice and acidified with 2N hydrochloric acid. Extraction with ethylacetate and evaporation gave a white solid which was dissolved indimethylsulphoxide (100 ml) and potassium carbonate (24 g) was added.After 1 h at room temperature, iodomethane (15 ml) was added and themixture was heated at 40° for 3 h. After cooling, the mixture was pouredin to ice and the precipitate was purified by chromatogaphy on silicagel eluting with toluene/ethyl acetate (90/10) to give the titlecompound (11.5 g) as a solid, mp: 88°.

INTERMEDIATE 22

5-Benzoyl-2-methoxybenzoic acid

To a suspension of Intermediate 21 (7 g) in water (45 ml) was addedpotassium hydroxide (4.3 g) and the mixture was heated at reflux for 2h. After cooling, the solution was acidified with 1N hydrochloric acidand the white precipitate was filtered off and dried to give the titlecompound (6.1 g) as a solid, mp: 150°.

INTERMEDIATE 23

Methyl 5-(3-methoxybenzoyl)-2-methoxybenzoate

Aluminium trichloride (9.4 g) and 3-methoxybenzoyl chloride (5 ml) wereadded to 1,2-dichloroethane (60 ml) at room temperature. The mixture wascooled to -5° and salicylic acid (4.8 g) was added portionwise and themixture was heated to 40°. After 12 h at 40°, the mixture was cooled,poured into ice and acidified with 2N hydrochloric acid. Extraction withethyl acetate and evaporation gave an oil which was dissolved indimethylsulphoxide (50 ml) and potassium carbonate (20 g) was added.After 1 h at room temperature, iodomethane (10 ml) was added and themixture was heated at 40° for 3 h. After cooling, the mixture was pouredinto ice and the oil was purified by chromatogaphy eluting withtoluene/ethyl acetate (90/10) to give the title compound (4.1 g), as anyellow oil.

INTERMEDIATE 24

5-(3-Methoxybenzoyl)-2-methoxybenzoic acid

To a suspension of Intermediate 23 (3.5 g) in water (40 ml) was addedpotassium hydroxide (1.9 g) and the mixture was heated at reflux for 2h. After cooling, the solution was acidified with 1N hydrochloric acidand the white precipitate was filtered off and dried to give the titlecompound (2.5 g) as a solid, mp: 132°.

EXAMPLE 1

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolin)propyl]phenyl]-2-quinoxalinecarboxamide

A mixture of 2-quinoxalinecarboxylic acid (0.5 g) and1-hydroxybenzotriazole (0.39 g) in DMF (20 ml) was stirred at roomtemperature for 10 min.4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (0.78 g) was then added, followed bydicyclohexylcarbodiimide (0.59 g) and the mixture was stirred at roomtemperature for 16 h and then filtered. The filtrate was concentrated invacuo, treated with dilute sodium hydroxide solution and extracted withmethylene chloride. The combined, dried, organic extracts wereevaporated and the residue was purified by column chromatography onsilica gel eluting with methylene chloride/methanol (9:1) to give thetitle compound (0.62 g) as a white solid, after crystallisation frommethanol, mp=155°.

Analysis Found: C, 71.41; H, 6.20; N, 11.62; C₂₉ H₃₀ N₄ O₃ (0.25H₂ O)Requires: C, 71.51; H, 6.31; N, 11.50%.

The following compounds were prepared in a similar manner:

EXAMPLE 2

N-[4-(3-(Methylveratrylamino)propyl)phenyl]-2-(4-methoxyphenyl)-4-quinolinecarboxamide

The coupling of 2-(4-methoxyphenyl)-4-quinolinecarboxylic acid (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.9 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.75 g), mp=105°.

Analysis Found: C, 75.24; H, 6.49; N, 7.20; C₃₆ H₃₇ N₃ O₄ Requires: C,75.10; H, 6.48; N, 7.30%.

EXAMPLE 3

N-[4-(2-(Methylveratrylamino)ethoxy)phenyl]-2-(3-methoxyphenyl)-4-quinolinecarboxamide

The coupling of 2-(3-methoxyphenyl)-4-quinolinecarboxylic acid (0.8 g)withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 36(b) in EP-A-494623) (0.78 g) gave, after crystallisationfrom diisopropyl ether, the title compound as a solid (0.36 g) mp=97°.

Analysis Found: C, 72.55; H, 6.08; N, 7.23; C₃₅ H₃₅ N₃ O₅ Requires: C,72.77; H, 6.11; N, 7.27%.

EXAMPLE 4

N-[4-[2-[(4-Methoxybenzyl)methylamino]ethoxy]phenyl]-6-methyl-2-phenyl-4-quinolinecarboxamide

The coupling of 6-methyl-2-phenyl-4-quinolinecarboxylic acid (1.32 g)with N-[2-(4-aminophenoxy)ethyl]-4-methoxy-N-methylbenzenemethanamine(Intermediate 36(f) in EP-A-494623) (1.2 g) gave the title compound asan oil (0.6 g) in the form of an oxalate (from isopropanol),mp=180°-182°.

Analysis Found : C, 67.66; H, 5.78; N, 6.91; C₃₄ H₃₃ N₃ O₃, C₂ H₂ O₄,Hb2O Requires: C, 67.59; H, 5.83; N, 6.57%.

EXAMPLE 5

N-[4-[2-[(4-Methoxybenzyl)methylamino]ethoxy]phenyl]-6-methoxy-2-phenyl-4-quinolinecarboxamide

The coupling of 6-methoxy-2-phenyl-4-quinolinecarboxylic acid (0.84 g)with N-[2-(4-aminophenoxy)ethyl]-4-methoxy-N-methylbenzenemethanamine(Intermediate 36(f) in EP-A-494623) (0.87 g) gave after crystallisationfrom methanol, the title compound as a solid (0.25 g), mp=114°-115°.

Analysis Found: C, 73.94; H, 6.06; N, 7.81; C₃₄ H₃₃ N₃ O₄ Requires: C,74.56; H, 6.07; N, 7.67%.

EXAMPLE 6

N-[4-(4-(Methylveratrylamino)butyl)phenyl]-6-methoxy-2-phenyl-4-quinolinecarboxamide

The coupling of 6-methoxy-2-phenyl-4-quinolinecarboxylic acid (1.4 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenebutanamine(Intermediate 33(a) in EP-A-494623) (1.65 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.38 g), mp=148°.

Analysis Found: C. 75.26; H, 6.69; N, 6.73; C₃₇ H₃₉ N₃ O₄ Requires: C,75.74; H, 6.18; N, 7.16%.

EXAMPLE 7

N-[4-(2-(Methylveratrylamino)ethyl)phenyl]-1-phenothiazinecarboxamide

The coupling of 1-phenothiazinecarboxylic acid* (0.63 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzeneethanamine(Intermediate 33(b) in EP-A-494623) (0.78 g) gave the title compound asan oil (0.4 g) in the form of a hydrochloride (from diethyl ether),mp=144°.

Analysis Found: C, 64.36; H, 5.98; Cl, 5.24; N, 7.15; S, 5.60; C₃₁ H₃₁N₃ O₃ S₁, HCl, H₂ O Requires: C, 64.18; H, 5.91; Cl, 6.00; N, 7.24; S,5.53%.

EXAMPLE 8

N-[4-(2-(Methylveratrylamino)ethoxy)phenyl]-1-phenazinecarboxamide

The coupling of 1-phenazinecarboxylic acid* (0.68 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy)-N-methylbenzenemethanamine(Intermediate 36(b) in EP-A-494623) (1 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.55 g), mp=135°.

Analysis Found: C, 71.30; H, 5.78; N, 10.47; C₃₁ H₃₀ N₄ O₄ Requires: C,71.24; H, 5.78; N, 10.72%.

EXAMPLE 9

N-[4-[2-[(4-Methoxybenzyl)methylamino]ethoxy]phenyl]-1-phenazinecarboxamide

The coupling of 1-phenazinecarboxylic acid (0.68 g) withN-[2-(4-aminophenoxy)ethyl]-4-methoxy-N-methybenzenemethanamine(Intermediate 36(f) in EP-A-494623) (1 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.52 g), mp=134°.

Analysis Found: C, 72.89; H, 5.76; N, 11.54; C₃₀ H₂₈ N₄ O₃ Requires: C,73.15; H, 5.73; N, 11.37%.

EXAMPLE 10

N-[4-(2-(Methylhomoveratrylamino)ethoxy)phenyl]-1-phenothiazinecarboxamide

The coupling of 1-phenothiazinecarboxylic acid (0.73 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzeneethanamine(Intermediate 36(a) in EP-A-494623) (1.1 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.45 g), mp=90°.

Analysis Found: C, 68.98; H, 5.89; N, 7.49; S, 5.59; C₃₂ H₃₃ N₃ O₄ S₁Requires: C, 69.16; H, 5.98; N, 7.56; S, 5.77%.

EXAMPLE 11

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]phenyl]-3-isoquinolinecarboxamide

The coupling of 3-isoquinolinecarboxylic acid (0.6 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (1 g) gave, after trituration indiethyl ether, the title compound (0.89 g) as a solid, mp=146°.

Analysis Found: C, 73.87; H, 6.15; N, 8.60; C₃₀ H₃₁ N₃ O₃ Requires: C,73.44; H, 6.57; N, 8.56%.

EXAMPLE 12

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-6,7-dimethyl-2-quinoxalinecarboxamide

The coupling of 6,7-dimethyl-2-quinoxalinecarboxylic acid (0.45 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.68 g) gave, after crystallisationfrom isopropanol, the title compound (0.26 g) as a solid, mp=100°-105°.

Analysis Found: C, 70.82; H, 6.89; N, 10.23; C₃₂ H₃₆ N₄ O₃ (H₂ O)Requires: C, 70.82; H, 7.05; N, 10.32%.

EXAMPLE 13

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-6(7)-methyl-2-quinoxalinecarboxamide

The coupling of 6(7)-methyl-2-quinoxalinecarboxylic acid* (0.5 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (0.89 g) gave, after crystallisationfrom acetonitrile, the title compound (1 g) as a solid, mp=147°.

Analysis Found: C, 70.29; H, 6.33; N, 10.38; C₃₁ H₃₄ N₄ O₄ Requires: C,70.70; H, 6.51; N, 10.64%.

EXAMPLE 14

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]phenyl]-6(7)-methyl-2-quinoxalinecarboxamide

The coupling of 6(7)-methyl-2-quinoxalinecarboxylic acid (0.5 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (0.9 g) gave, after crystallisationfrom isopropanol, the title compound (1.05 g) as a solid, mp=120°-126°.

Analysis Found: C, 72.88; H, 6.89; N, 10.69; C₃₁ H₃₄ N₄ O₃ Requires: C,72.92; H, 6.71; N, 10.97%.

EXAMPLE 15

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-6(7)-methoxy-2-quinoxalinecarboxamide

The coupling of Intermediate 6 (0.54 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.9 g) gave, after crystallisationfrom a 1:1 mixture of isopropanol and acetonitrile, the title compound(0.93 g) as a solid, mp=138°.

Analysis Found: C, 69.49; H, 6.41; N, 10.30; C₃₁ H₃₄ N₄ O₄ (0.5H₂ O)Requires: C, 69.51; H, 6.59; N, 10.44%.

EXAMPLE 16

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-6(7)-methoxy-2-quinoxalinecarboxamide

The coupling of Intermediate 6 (0.54 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (0.89 g) gave, after crystallisationfrom a 1:1 mixture of isopropanol and acetonitrile, the title compound(0.9 g) as a solid, mp=166°.

Analysis Found: C, 67.24; H, 5.99; N, 10.48; C₃₀ H₃₂ N₄ O₅ (0.5H₂ O)Requires: C, 67.02; H, 6.18; N, 10.42%.

EXAMPLE 17

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]phenyl]-3-quinolinecarboxamide

The coupling of 3-quinolinecarboxylic acid (1 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (1.2 g) gave, after crystallisationfrom isopropanol, the title compound (1.01 g) as a solid, mp=184°-185°.

Analysis Found: C, 74.40; H, 6.50; N, 8.59; C₃₀ H₃₁ N₃ O₃ Requires: C,74.82; H, 6.49; N, 8.73%.

EXAMPLE 18

Hydrochloride salt ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-2-quinolinecarboxamide

The coupling of 2-quinolinecarboxylic acid (0.38 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.5 g) gave, after crystallisationfrom isopropanol, the title compound (0.23 g) as a solid, mp=230°-235°.

Analysis Found: C, 69.48; H, 6.45; N, 7.46; C₃₁ H₃₄ N₃ O₃ Requires: C,69.98; H, 6.44; N, 7.90%.

EXAMPLE 19

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]phenyl]-4-methoxy-2-quinolinecarboxamide

The coupling of 4-methoxy-2-quinolinecarboxylic acid (1 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (1 g) gave, after crystallisationfrom isopropanol, the title compound (0.5 g) as a solid, mp=123°-125°.

Analysis Found: C, 72.70; H, 6.58; N, 8.30; C₃₁ H₃₃ N₃ O₄ Requires: C,72.78; H, 6.50; N, 8.21%.

EXAMPLE 20

N-[4-[4-(Methylveratrylamino)butyl]phenyl]-2-quinoxalinecarboxamide

The coupling of 2-quinoxalinecarboxylic acid (0.5 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenebutanamine(intermediate 33(a) in EP-A-494623) (0.94 g) gave, after crystallisationfrom ethanol, the title Compound (0.4 g) as a solid, mp=82°-85°.

Analysis Found: C, 71.89; H, 6.73; N, 11.75; C₂₉ H₃₂ N₄ O₃ Requires: C,71.88; H, 6.66; N, 11.56%.

EXAMPLE 21

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-2-quinoxalinecarboxamide

The coupling of 2-quinoxalinecarboxylic acid (0.5 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.62 g) gave, after trituration withdiethyl ether, the title Compound (0.4 g) as a solid, mp=144°.

Analysis Found: C, 72.33; H, 6.55; C₃₀ H₃₂ N₄ O₃ Requires: C, 72.56; H,6.49%.

EXAMPLE 22

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-2-quinoxalinecarboxamide

The coupling of 2-quinoxalinecarboxylic acid (0.5 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623 (1 g) gave, after recrystallisationfrom ethanol, the title compound (0.78 g) as a solid, mp=170°-173°.

Analysis Found: C, 69.35; H, 6.16; N, 11.27; C₂₉ H₃₀ N₄ O₄ Requires: C,69.86; H, 6.06; N, 11.24%.

EXAMPLE 23

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-3-methoxy-6,7-dimethyl-2-quinoxalinecarboxamide

The coupling of Intermediate 3(a) (0.6 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623 (0.8 g) gave, after crystallisationfrom isopropanol, the title compound (0.47 g) as a solid, mp=158°.

Analysis Found: C, 67.32; H, 6.67; N, 9.80; C₃₂ H₃₆ N₄ O₅ (0.5H₂ O)Requires: C, 67.94; H, 6.59; N, 9.90%.

EXAMPLE 24

N-[4-[3-(1,2,3.4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]phenyl]-3-methoxy-6,7-dimethyl-2-quinoxalinecarboxamide

The coupling of Intermediate 3(a) (0.6 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (0.8 g) gave, after crystallisationfrom isopropanol, the title compound (0.75 g) as a solid, mp=164°-166°.

Analysis Found: C, 67.32; H, 6.67; N, 9.80; C₃₂ H₃₆ N₄ O₅ (0.5H₂ O)Requires: C, 67.94; H, 6.54; N, 9.90%.

EXAMPLE 25

N-[4-[4-(1,2,3,4-Tetrahydro-6.7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-3-methyl-2-quinoxalinecarboxamide

The coupling of 3-methyl-2-quinoxalinecarboxylic acid* (0.5 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.9 g) gave, after crystallisationfrom a 1:1 mixture of isopropanol and acetonitrile, the title compound(0.9 g) as a solid, mp=146°.

Analysis Found: C, 73.13; H, 6.76; N, 10.88; C₃₁ H₃₄ N₄ O₃ Requires: C,72.92; H, 6.71; N, 10.97%.

EXAMPLE 26

N-[4-[3-(Methylveratrylamino)propyl]phenyl]-5-methoxyindole-2-carboxamide

The coupling of 5-methoxyindole-2-carboxylic acid (0.5 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.62 g) gave, after crystallisationfrom isopropanol, the title compound (0.48 g) as a solid, mp=80°.

Analysis Found: C, 70.79; H, 6.86; N, 8.02; C₂₉ H₃₃ N₃ O₄ (0.25H₂ O)Requires: C, 70.78; H, 6.86; N, 8.03%.

EXAMPLE 27

N-[4-[3-(Methylveratrylamino)propyl]phenyl]-3-benzoyl-2-indolecarboxamide

The coupling of 3-benzoyl-2-indolecarboxylic acid (0.35 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.42 g) gave, after crystallisationfrom ethanol, the title compound (0.30 g) as a solid, mp=156°-161°.

Analysis Found: C, 74.25; H, 6.36; N, 7.05; C₃₅ H₃₅ N₃ O₄ (0.25H₂ O)Requires: C, 74.24; H, 6.32;,N, 7.42%.

EXAMPLE 28

N-[4-[3-(Methylveratrylamino)propyl]phenyl]-1-naphtalenecarboxamide

The coupling of 1-naphthoic acid (0.3 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.53 g) gave, after crystallisationfrom diisopropyl ether, the title compound (0.38 g) as a solid, mp:113°-117°.

Analysis Found: C, 75.84; H, 6.93; N, 5.92; C₃₀ H₃₂ N₂ O₃.0.4H₂ ORequires: C, 75.73; H, 6.94; N, 5.88%.

EXAMPLE 29

Oxalate ofN-[4-[3-methylveratrylamino]propyl]phenyl]-2-naphtalenecarboxamide

The coupling of 2-naphthoic acid (0.4 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.73 g) gave the title compound(0.6 g) as a solid, mp: 203°-207°.

Analysis Found: C, 68.76; H, 6.17; N, 5.04; C₃₀ H₃₂ N₂ O₃.C₂ H₂ O₄Requires: C, 68.80; H, 6.13; N, 5.01%.

EXAMPLE 30

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-2-naphtalenecarboxamide

The coupling of 2-naphthoic acid (0.6 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.79 g) gave, after crystallisationfrom isopropanol, the title compound (0.5 g) as a solid, mp: 165°-167°.

Analysis Found : C, 76.84; H, 6.92; N, 5.59; C₃₂ H₃₄ N₂ O₃.0.3H₂ ORequires: C, 76.86; H, 6.97; N, 5.60%.

EXAMPLE 31

N-[4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-2isoquinolinyl)ethyl]phenyl]-2-naphtalenecarboxamide

The coupling of 2-naphthoic acid (0.47 g) with4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]benzenamine(Intermediate 2(c) in EP-A-494623) (0.82 g) gave, after crystallisationfrom isopropanol, the title compound (0.83 g) as a solid, mp: 162°-165°.

Analysis Found : C, 77.28; H, 6.50; N, 5.91; C₃₀ H₃₀ N₂ O₃ Requires: C,77.23; H, 6.48; N, 6.00%.

EXAMPLE 32

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-2-naphtalenecarboxamide

The coupling of 2-naphthoic acid (0.3 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (0.58 g) gave, after crystallisationfrom acetonitrile, the title compound (0.2 g) as a solid, mp: 189°-190°.

Analysis Found: C, 74.97; H, 6.53; N, 5.54; C₃₁ H₃₂ N₂ O₄ Requires: C,74.98; H, 6.50; N, 5.64%.

EXAMPLE 33

N-[4-[3-(Methylveratrylamino)propoxy]phenyl]-2-naphtalenecarboxamide

The coupling of 2-naphthoic acid (0.4 g) withN-[3-(4-aminophenoxy)propyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 38(c) in EP-A-494623) (0.76 g) gave, after crystallisationfrom acetonitrile, the title compound (0.45 g) as a solid, mp:131°-133°.

Analysis Found: C, 74.22; H, 6.75; N, 5.78; C₃₀ H₃₂ N₂ O₄ Requires: C,74.36; H, 6.66; N, 5.78%.

EXAMPLE 34

Oxalate ofN-[4-[3-methylveratrylamino]propyl]phenyl]-1-isoquinolinecarboxamide

The coupling of 1-isoquinolinecarboxylic acid (0.35 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(c) in EP-A-494623) (0.53 g) gave the title compound(0.3 g) as a solid, mp: 183°-187°.

Analysis Found: C, 66.65; H, 6.00; N, 7.40; C₂₉ H₃₁ N₃ O₃.C₂ H₂ O₄Requires: C, 66.53; H, 5.94; N, 7.51%.

EXAMPLE 35

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-1-isoquinolinecarboxamide

The coupling of 1-isoquinolinecarboxylic acid (0.35 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (0.58 g) gave, after crystallisationfrom isopropanol, the title compound (0.6 g) as a solid, mp: 160°.

Analysis Found: C, 72.61; H, 6.39; N, 8.43; C₃₀ H₃₁ N₃ O₄ Requires: C,72.41; H, 6.28; N, 8.44%.

EXAMPLE 36

Oxalate ofN-[4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]phenyl]-1-isoquinolinecarboxamide

The coupling of 1-isoquinolinecarboxylic acid (0.35 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]benzenamine(Intermediate 5(b) in EP-A-494623) (0.55 g) gave the title compound (0.5g) as a solid, mp: 206°-209°.

Analysis Found: C, 66.56; H, 5.87; N, 7.30; C₃₀ H₃₁ N₃ O₃ C₂ H₂ O₄ 0.3H₂O Requires: C, 66.60; H, 5.87; N, 7.28%.

EXAMPLE 37

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-3(2-methoxybenzoyl)benzamide

The coupling of Intermediate 8 (0.56 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.67 g) gave the title compound(0.31 g) as an amorphous solid, mp=78°.

Analysis Found: C, 71.35; H, 6.68; N, 4.82; C₃₆ H₃₈ N₂ O₅ 1.5H₂ ORequires: C, 71.38; H, 6.82; N, 4.62%

EXAMPLE 38

Fumarate ofN-[4-[3-methylveratrylamino]propyl]phenyl]-2-indolecarboxamide

The coupling of 2-indolecarboxylic acid (0.3 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.58 g) gave the title compound(0.3 g) as a solid, mp=196°.

Analysis Found: C, 69.79; H, 6.36; N, 8.21; C₂₈ H₃₁ N₃ O₃ C₄ H₄ O₄Requires: C, 69.88; H, 6.45; N, 8.15%.

EXAMPLE 39

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butoxy]phenyl]-6(7)-methyl-2-quinoxalinecarboxamide

The coupling of 6(7)-methyl-2-quinoxalinecarboxylic acid (0.5 g) withIntermediate 11(b) (0.94 g) gave, after crystallisation from a 1:1mixture of isopropanol and acetonitrile, the title compound (1.09 g) asa solid, mp=142°-148°.

Analysis Found: C, 70.86; H. 6.49; N, 10.40; C₃₁ H₃₄ N₄ O₄ Requires: C,70.70; H, 6.51; N, 10.64%.

EXAMPLE 40

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butoxy]phenyl]-1-isoquinolinecarboxamide

The coupling of 1-isoquinolinecarboxylic acid (0.5 g) with Intermediate11(b) (0.89 g) gave, after crystallisation from methanol, the titlecompound (0.6 g) as a solid, mp=122°-123°.

Analysis Found: C, 72.73; H, 6.62; N, 8.12; C₃₁ H₃₃ N₃ O₄ Requires: C,72.78; H, 6.50; N, 8.21%.

EXAMPLE 41

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butoxy]phenyl]-2-quinoxalinecarboxamide

The coupling of 2-quinoxalinecarboxylic acid (0.5 g) with Intermediate11(b) (0.89 g) gave, after crystallisation from acetonitrile, the titlecompound (0.97 g) as a solid, mp=141 °.

Analysis Found: C, 69.62; H, 6.29; N, 10.93; C₃₀ H₃₂ N₄ O₄ (0.3H₂ O)Requires: C, 69.55; H, 6.34; N, 10.81%.

EXAMPLE 42

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butoxy]phenyl]-3-ethoxy-2-quinoxalinecarboxamide

The coupling of 3-ethoxy-2-quinoxalinecarboxylic acid (0.5 g) withIntermediate 11(b) (0.63 g) gave, after crystallisation from ethanol,the title compound (0.48 g) as a solid, mp=182°.

Analysis Found: C, 72.08; H, 4.51; N, 16.86; C₁₈ H₁₁ N₃ O Requires: C,72.28; H, 4.45; N, 16.86%.

EXAMPLE 43

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl:)butoxy]phenyl]-4-[2-(4-chlorophenyl)-3-trifluoromethylpyrazole]carboxamide

The coupling of 2-(4-chlorophenyl)-3-trifluoromethylpyrazole-4-carboxlicacid (1 g) with Intermediate 11(b) (1.3 g) gave the title compound (1.8g), mp=153°.

Analysis Found: C, 60.87; H, 5.11; N, 8.77; C₃₂ H₃₂ ClF₃ N₄ O₄ Requires:C, 61.10; H, 5.13; N, 8.91%.

EXAMPLE 44

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butoxy]phenyl]-5-[4-methyl-2-[4-trifluoromethyl)phenyl]thiazole]carboxamide

The coupling of4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole-5-carboxylic acid (1 g)with Intermediate 11(b) (1 g) gave, after crystallisation frommethanol/ethanol (1:1), the title compound (0.7 g), mp=160°-180°.

Analysis Found: C, 62,95; H, 5.33; F, 9.06;, N,6.52; C₃₃ H₃₄ F₃ N₃ O₄ SRequires: C, 63.35; H, 5.48; F, 9.11; N, 6.72%.

EXAMPLE 45

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-2-[5-(2-pyridyl)lthiophene]carboxamide

The coupling of 5-(2-pyridyl)thiophene-2-carboxylic acid (1 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (1.3 g) gave, after crystallisationfrom methanol, the title compound (1.5 g), mp=196°.

Analysis Found: C, 67.96; H, 5.88; N, 7.86; C₃₀ H₃₁ N₃ O₄ S Requires: C,68.03; H, 5.90; N, 7.93%.

EXAMPLE 46

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-4-[2-(3-pyridyl)thiazole]carboxamide

The coupling of 2-(3-pyridyl)thiazole-4-carboxylic acid (1 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) gave, after crystallisation fromisopropanol/methanol, the title compound (1.2 g), mp=125°.

Analysis Found: C, 65,30; H, 5.11; N, 10.32; C₂₉ H₃₀ N₄ O₄ S Requires:C, 65.64; H, 5.70; N, 10.56%

EXAMPLE 47

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-5-(4-methyl-2-phenyl-1,2,3-triazole)carboxamide

The coupling of 4-methyl-2-phenyl-1,2,3-triazole-5-carboxylic acid (1 g)with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (1.6 g) gave, after crystallisationfrom methanol/pyridine (5:1) the title compound (1.6 g), mp=146°.

Analysis Found: C, 67.28; H, 6.10; N, 13.20; C₃₀ H₃₃ N₅ O₄ (0.5H₂ O)Requires: C, 67.14; H, 6.38; N, 13.05%.

EXAMPLE 48

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-2-hydroxypropoxy]phenyl]-2-quinoxalinecarboxamide

The coupling of 2-quinoxalinecarboxylic acid (0.5 g) with Intermediate13 (1 g) gave the title compound (0.9 g) as a solid, mp=158°-160°.

Analysis Found: C, 65.68; H, 5.99; N, 10.23; C₂₉ H₃₀ N₄ O₅ (1H₂ O)Requires: C, 65.40; H, 6.05; N,10.52%.

EXAMPLE 49

N-[4-(2-(Methylveratrylamino)ethyl)phenyl]-2-(4-methoxyphenyl)-4-quinolinecarboxamide

The coupling of 2-(4-methoxyphenyl)-4-quinolinecarboxylic acid (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzeneethanamine(Intermediate 33(b) in EP-A-494623) (0.86 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.33 g), mp=114°.

Analysis Found: C, 74.72; H, 6.29; N, 7.29; C₃₅ H₃₅ N₃ O₄ Requires: C,74.84; H, 6.28; N, 7.48%.

EXAMPLE 50

N-[4-(3-(Methylveratrylamino)propyl)phenyl]-2-(3-methoxyphenyl)-4-quinolinecarboxamide

The coupling of 2-(3-methoxyphenyl)-4-quinolinecarboxylic acid (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.9 g) gave, after crystallisationfrom isopropanol, the title compound as a solid (0.51 g), mp=110°.

Analysis Found: C, 75.10; H, 6.52; N, 7.26; C₃₆ H₃₇ N₃ O₄ Requires: C,75.10; H, 6.48; N, 7.30%.

EXAMPLE 51

N-[4-[2-(Methylveratrylamino)ethyl]phenyl)-9-oxo-4-thioxanthenecarboxamide

A mixture of 9-oxo-4-thioxanthenecarboxylic acid* (0.8 g) and1-hydroxybenzotriazole (0.42 g) in DMF (20 ml) was stirred at roomtemperature for 10 min.4-Amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenemethanamine(Intermediate 33(b) in EP-A-494623) (0.94 g) in DMF (20 ml) was thenadded, followed by dicyclohexylcarbodiimide (0.64 g) and the mixture wasstirred at room temperature for 16 h and then filtered. The filtrate wasconcentrated in vacuo, treated with dilute sodium hydroxide solution andextracted with dichloromethane. The combined dried organic extracts wereevaporated to leave an oil which was purified by column chromatographyeluting with dichloromethane: methanol (95:5). The resulting solid wasrecrystallised from acetonitrile and filtered off to give the titlecompound as a solid (0.26 g),mp=180°.

Analysis Found: C, 71.02; H, 5.59; N, 5.18; S, 5.78; C₃₂ H₃₀ N₂ O₄ S₁Requires: C, 71.35; H, 5.61; N, 5.20; S, 5.95%.

The following examples were prepared in a similar manner:

EXAMPLE 52

N-[4-(3-(Methylveratrylamino)propyl)phenyl]-5-methoxy-9-oxo-4-thioxanthenecarboxamide

The coupling of 5-methoxy-9-oxo-4-thioxanthenecarboxylic acid* (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.88 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.12 g), mp=144°-146°.

Analysis Found: C, 69.49; H, 5.86; N, 4.75; S, 5.33; C₃₄ H₃₄ N₂ O₅ S₁Requires: C, 70.08; H, 5.88; N, 4.81; S, 5.50%.

EXAMPLE 53

N-[4-(2-(Methylveratrylamino)ethyl)phenyl]-5-methoxy-9-oxo-4-thioxanthenecarboxamide

The coupling of 5-methoxy-9-oxo-4-thioxanthenecarboxylic acid (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzeneethanamine(Intermediate 33(b) in EP-A-494623) (0.8 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.1 g) mp=151°.

Analysis Found: C. 67.98; H, 5.66; N, 4.79; S, 5.29; C₃₃ H₃₂ N₂ O₅ S₁,H₂O Requires: C, 67.55; H, 5.84; N, 4.77; S, 5.46%.

EXAMPLE 54

N-[4-(3-(Methylveratrylamino)propoxy)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) with4-amino-N-[[(3,4-dimethoxyphenyl)methyl]-N-methylbenzeneethanamine(Intermediate 33(b) in EP-A-494623) (1 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.47 g), mp=184°.

Analysis Found: C, 69.67; H, 5.68; N, 4.93; S, 5.52; C₃₃ H₃₂ N₂ O₅ S₁Requires: C, 69.69; H, 5.67; N, 4.93; S, 5.64%.

EXAMPLE 55

N-[4-(2-(Methylveratrylamino)ethyl)phenyl]-7-fluoro-9-oxo-4-thioxanthenecarboxamide

The coupling of 7-fluoro-9-oxo-4-thioxanthenecarboxylic acid* (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzeneethanamine(Intermediate 33(b) in EP-A-494623) (0.87 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.3 g), mp=205°.

Analysis Found: C, 68.99; H, 5.23; F, 3.31; N, 4.99; S, 5.58; C₃₂ H₂₉ F₁N₂ O₄ S₁ Requires: C, 69.04; H, 5.25; F, 3.41; N, 5.03; S, 5.76%.

EXAMPLE 56

N-[4-(3-(Methylveratrylamino)propyl)phenyl]-7-fluoro-9-oxo-4-thioxanthenecarboxamide

The coupling of 7-fluoro-9-oxo-4-thioxanthenecarboxylic acid (0.8 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.9 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.3 g) mp=160°.

Analysis Found: C, 69.24; H, 5.46; F, 3.20; N, 4.85; S, 5.49; C₃₃ H₃₁ F₁N₂ O₄ S₁ Requires: C, 69.45; H, 5.48; F, 3.33; N, 4.91; S, 5.62%.

EXAMPLE 57

N-[4-(4-(1Methylveratrylamino)butyl)phenyl]-7-fluoro-9-oxo-4-thioxanthenecarboxamide

The coupling of 7-fluoro-9-oxo-4-thioxanthenecarboxylic acid (0.4 g)with 4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenebutanamine(Intermediate 33(a) in EP-A-494623) (0.48 g) gave, after crystallisationfrom ethanol the title compound as a solid (0.076 g), mp=168°.

Analysis Found: C, 69.80; H, 5.77; F, 3.24; N, 4.66; S, 5.42; C₃₄ H₃₃ F₁N₂ O₄ S₁ Requires: C, 69.84; H, 5.69; F, 3.25; N, 4.79; S, 5.48%.

EXAMPLE 58

N-[4-(3-(Methylveratrylamino)propylthio)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) withN-[3-[(4-aminophenyl)thio]propyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 38(d) in EP-A-494623) (1 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.1 g), mp=148°.

Analysis Found: C, 67.73; H, 5.35; N, 4.71; S, 10.85; C₃₃ H₃₂ N₂ O₄ S₂Requires: C, 67.78; H, 5.52; N, 4.79; S, 10.96%.

EXAMPLE 59

N-[4-(Methylveratrylamino)methyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) withIntermediate 11(d) (0.9 g) gave, after crystallisation from ethanol, thetitle compound as a solid (0.1 g), mp=166°.

Analysis Found: C, 70.85; H, 5.38; N, 5.50; S, 5.90; C₃₁ H₂₈ N₂ O₄ S₁Requires: C, 70.97; H, 5.38; N, 5.34; S, 6.11%.

EXAMPLE 60

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (1.14 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.35 g), mp=210°.

Analysis Found: C, 70.29; H, 5.51; N, 4.89; S, 5.52; C₃₄ H₃₂ N₂ O₅ S₁Requires: C, 70.32; H, 5.55; N, 4.83; S, 5.52%.

EXAMPLE 61

N-[4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-5-methoxy-9-oxo-4-thioxanthenecarboxamide

The coupling of 5-methoxy-9-oxo-4-thioxanthenecarboxylic acid (3 g) with4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]benzenamine(Intermediate 2(c) in EP-A-494623) (3 g) gave, after crystallisationfrom methanol, the title compound as a solid (1.38 g), mp=218°-219°.

NMR includes signals at δ2.8(4H,m,N-(CH₂)₂ -Ph); 3.7(6H,s,2OCH₃);3.8(3H,s,OCH₃).

EXAMPLE 62

N-[4-(2-Methylhomoveratrylamino)ethoxy)phenyl]-9-oxo-4-xanthenecarboxamide

The coupling of 9-oxo-4-xanthenecarboxylic acid (0.33 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzeneethanamine(Intermediate 36(a) in EP-A-494623) (0.45 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.15 g), mp=152°.

Analysis Found: C, 71.54; H, 5.85; N, 5.07; C₃₃ H₃₂ N₂ O₆ Requires: C,71.72; H, 5.84; N, 5.07%.

EXAMPLE 63

N-[4-(2-(Methylhomoveratrylamino)ethoxy)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzeneethanamine(Intermediate 36(a) in EP-A-494623) (1 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.35 g), mp=168°.

Analysis Found: C, 69.71; H, 5.67; N, 4.91; S, 5.50; C₃₃ H₃₂ N₂ O₅ S₁Requires: C, 69.69; H, 5.67; N, 4.93; S, 5.64%.

EXAMPLE 64

N-[4-(2-(Methylveratrylamino)ethoxy)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (1 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 36(b) in EP-A-494623) (1.23 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.2 g), mp=188°.

Analysis Found: C, 68.89; H, 5.75; N, 5.50; S, 5.46; C₃₂ H₃₀ N₂ O₅ S₁Requires: C. 69.29; H, 5.46; N, 5.05; S, 5.78%.

EXAMPLE 65

N-[4-(3-(Methylhomoveratrylamino)propoxy)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) withN-[3-(4-aminophenoxy)propyl]-3,4-dimethoxy-N-methylbenzeneethanamine(Intermediate 38(a) in EP-A-494623) (1 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.6 g), mp=174°.

Analysis Found: C, 69.70; H, 5.89; N, 4.70; S, 5.39; C₃₄ H₃₄ N₂ O₅ S₁Requires: C, 70.08; H, 5.88; N, 4.81; S, 5.50%.

EXAMPLE 66

N-[4-(4-(Methylveratrylamino)butyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.77 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenebutanamine(Intermediate 33(a) in EP-A-494623) (0.98 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.27 g), mp=156°.

Analysis Found: C, 71.82; H, 6.00; N, 5.06; S, 5.63; C₃₄ H₃₄ N₂ O₄ S₁Requires: C, 72.05; H, 6.05; N, 4.94; S, 5.66%.

EXAMPLE 67

N-[4-(4-(Methylhomoveratrylamino)butyl)phenyl]-7-fluoro-9-oxo-4-thioxanthenecarboxamide

The coupling of 7-fluoro-9-oxo-4-thioxanthenecarboxylic acid (1 g) with4-amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylbenzenebutanamine(Intermediate 33(c) in EP-A-494623) (1.25 g) gave, after crystallisationfrom ethanol, the title Compound as a solid (0.95 g), mp=145°.

Analysis Found: C, 69.87; H, 5.79; F, 2.95; N, 4.30; S, 5.35; C₃₅ H₃₅ F₁N₂ O₄ S₁ Requires: C, 70.21; H, 5.89; F, 3.17; N, 4.68; S, 5.35%.

EXAMPLE 68

N-[4-(2-(Methylhomoveratrylamino)ethoxy)phenyl]-7-fluoro-9-oxo-4-thioxanthenecarboxamide

The coupling of 7-fluoro-9-oxo-4-thioxanthenecarboxylic acid (1 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzeneethanamine(Intermediate 36(a) in EP-A-494623) (1.2 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.72 g), mp=145°.

Analysis Found: C, 67.42; H, 5.26; F, 2.92; N, 4.92; S, 5.85; C₃₃ H₃₁ F₁N₂ O₅ S₁ Requires: C, 67.56; H, 5.33; F, 3.24; N, 4.77; S, 5.46%.

EXAMPLE 69

N-[4-(2-(Methyveratrylamino)ethoxy)phenyl]-9-oxo-4-xanthenecarboxamide

The coupling of 9-oxo-4-xanthenecarboxylic acid (0.6 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 36(b) in EP-A-494623) (0.79 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.21 g), mp=110°.

Analysis Found: C, 71.17; H, 5.59; N, 5.29; C₃₂ H₃₀ N₂ O₆ Requires: C,71.36; H, 5.62; N, 5.20%.

EXAMPLE 70

N-[4-(2-(Methylhomoveratrylamino)ethyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) with4-amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylbenzeneethanamine(Intermediate 33(e) in EP-A-494623) (1 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.43 g), mp=154°.

Analysis Found: C, 71.83; H, 5.92; N, 5.08; S, 5.89; C₃₃ H₃₂ N₂ O₄ S₁Requires: C, 71.71; H, 5.84; N, 5.07; S, 5.80%.

EXAMPLE 71

N-[4-(4-(Methylhomoveratrylamino)butyl)phenyl]-9-oxo-4-xanthenecarboxamide

The coupling of 9-oxo-4-xanthenecarboxylic acid (0.3 g) with4-amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylbenzenebutanamine(Intermediate 33(c) in EP-A-494623) (0.42 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.09 g), mp=102°.

Analysis Found: C, 73.58; H, 6.36; N, 5.07; C₃₅ H₃₆ N₂ O₅ Requires: C,74.44; H, 6.43; N, 4.96%.

EXAMPLE 72

N-[4-(3-(Methylhomoveratrylamino)propoxy)phenyl]-9-oxo-4-xanthenecarboxamide

The coupling of 9-oxo-4-xanthenecarboxylic acid (0.6 g) withN-[3-(4-aminophenoxy)propyl]-3,4-dimethoxy-N-methylbenzeneethanamineIntermediate 38(a) in EP-A-494623) (1.04 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.26 g), mp=126°.

Analysis Found: C, 71.27; H, 6.06; N, 4.84; C₃₄ H₃₄ N₂ O₆ Requires: C,72.07; H, 6.05; N, 4.94%.

EXAMPLE 73

N-[4-[4-[(4-Methylthiobenzyl)methylamino]butyl]phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.8 g) with4-amino-N-[[4-(methylthio)phenyl]methyl]-N-methylbenzenebutanamine(Intermediate 33(j) in EP-A-494623) (1 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.39 g), mp=167°.

Analysis Found: C, 71.47; H, 5.78; N, 5.13; S, 11.50; C₃₃ H₃₂ N₂ O₂ S₂Requires: C, 71.70; H, 5.84; N, 5.07; S, 11.60%.

EXAMPLE 74

N-[4-[3-[(4-Methoxybenzyl)methylamino]propyl]phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.77 g) with4-amino-N-[(4-methoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(g) in EP-A-494623) (0.85 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.34 g), mp=170°.

Analysis Found: C, 73.22; H, 5.84; N, 5.35; S, 5.89; C₃₂ H₃₀ N₂ O₃ S₁Requires: C, 73.53; H, 5.78; N, 5.36; S, 6.13%.

EXAMPLE 75

N-[4-(3-(Methylhomoveratrylamino)propyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.6 g) with4-amino-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylbenzenepropanamine(Intermediate 33(d) in EP-A-494623) (1 g) gave, after crystallisationfrom acetonitrile, the title compound as a solid (0.35 g), mp=143°.

Analysis Found: C, 72.10; H, 5.91; N, 4.70; S, 5.48; C₃₄ H₃₄ N₂ O₄ S₁Requires: C, 72.06; H, 6.05; N, 4.94; S, 5.66%.

EXAMPLE 76

N-N-[2-[(4-Methoxyphenethyl)methylamino]ethyl]phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.4 g) with4-amino-N-[2-(4-methoxyphenyl)ethyl]-N-methylbenzeneethanamine(Intermediate 33(k) in EP-A-494823) (0.44 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.13 g), mp=163°.

Analysis Found: C, 72.49; H, 5.80; N, 5.35; S, 5.97; C₃₂ H₃₀ N₂ O₃ S₁Requires: C, 73.53; H, 5.79; N, 5.36; S, 6.13%.

EXAMPLE 77

N-[4-(5-(Methylveratrylamino)pentyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.4 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepentanamine(Intermediate 33(I) in EP-A-494623) (0.53 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.2 g), mp=166°.

Analysis Found: C, 72.31; H, 6.22; N, 4.85; S, 5.39; C₃₅ H₃₆ N₂ O₄ S₁Requires: C, 72.38; H, 6.25; N, 4.82; S, 5.52%.

EXAMPLE 78

N-[4-(3-(Methylveratrylamino)propyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (3 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (3.7 g) gave, after crystallisationfrom ethanol, the title compound as a solid (2.5 g), mp=150°.

Analysis Found: C, 71.70; H, 5.88; N, 5.06; S, 5.72; C₃₃ H₃₂ N₂ O₄ S₁Requires: C, 71.71; H, 5.84; N, 5.07; S, 5.80%.

EXAMPLE 79

N-[4-[3-(Methylveratrylamino)propyl]phenyl]-9-fluorenone-4-carboxamide

The coupling of 9-fluorenone-4-carboxylic acid (0.5 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.63 g) gave, after crystallisationfrom ethanol, the title compound (0.75 g) as a solid, mp=50°-75°.

Analysis Found: C, 75.12; H, 6.38; N, 5.23; C₃₃ H₃₂ N₂ O₄ (0.4H₂ O)Requires: C, 75.09; H, 6.26; N, 5.23%.

EXAMPLE 80

Fumarate ofN-[4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propylthio]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.5 g) with4-[[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propyl]thio]benzenamine(Intermediate 2(b) in EP-A-494623) (0.79 g) gave the title compound (0.4g) as a solid, mp: 192°.

Analysis Found: C, 66.94; H, 5.68; N, 4.07; C₃₄ H₃₄ N₂ O₄ S.C₄ H₄ ORequires: C, 66.85; H, 5.61; N, 4. 10%.

EXAMPLE 81

Oxalate ofN-[4-[3-(methylveratrylamino)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.8 g) withN-[3-(4-aminophenoxy)propyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 38(c) in EP-A-494623) (1.17 g) gave the title compound(1.2 g) as a solid, mp: 168°.

Analysis Found: C, 66.92; H, 5.79; N, 4.42; C₃₃ H₃₄ N₂ O₅.C₂ H₂ O₄Requires: C, 66.87; H, 5.77; N, 4.46%.

EXAMPLE 82

Fumarate ofN-[4-[4-(methylveratrylamino)]butyl]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.8 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenebutanamine(Intermediate 33(a) in EP-A-494623) (1.16 g) gave the title compound(1.2 g) as a solid, mp: 182°.

Analysis Found: C, 70.06; H, 6.19; N, 4.22; C₃₄ H₃₆ N₂ O₄.C₄ H₄ O₄Requires: C, 69.92; H, 6.18; N, 4.29%.

EXAMPLE 83

N-[4-[2-(Methylveratrylamino)ethyl]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.22 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzeneethanamine(Intermediate 33(b) in EP-A-494623) (0.3 g) gave, after crystallisationfrom diisopropyl ether, the title compound (0.28 g) as a solid, mp:130°.

Analysis Found: C, 75.19; H, 6.37; N, 5.50; C₃₂ H₃₂ N₂ O₄ Requires: C,75.57; H, 6.34; N, 5.51%.

EXAMPLE 84

Fumarate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.8 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (1.2 g) gave the title compound (0.3g) as a solid, mp: 198°.

Analysis Found: C, 70.36; H, 6.03; N, 4.08; C₃₅ H₃₆ N₂ O₄.C₄ H₄ O₄Requires: C, 70.46; H, 6.06; N, 4.21%.

EXAMPLE 85

N-[4-[3-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (1 g) with4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]benzenamine(Intermediate 2(a) in EP-A-494623) (1.5 g) gave, after crystallisationfrom isopropanol, the title compound (1.3 g) as a solid, mp:>260°.

Analysis Found: C, 74.12; H, 6.18; N, 5.16; C₃₄ H₃₄ N₂ O₅ Requires: C,74.15; H, 6.22; N, 5.08%.

EXAMPLE 86

Oxalate ofN-[2-methoxy-4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.6 g) with Intermediate 11(a)(0.98 g) gave the title compound (1 g) as a solid, mp: 158°.

Analysis Found: C, 66.29; H, 5.72; N, 4.10; C₃₅ H₃₆ N₂ O₆.C₂ H₂ O₄Requires: C, 66.26; H, 5.71; N, 4.18%.

EXAMPLE 87

Fumarate ofN-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.6 g) with4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]benzenamine(Intermediate 2(c) in EP-A-494623) (0.82 g) gave the title compound (1g) as a solid, mp: 134°.

Analysis Found: C, 70.87; H, 5.84; N, 4.33; C₃₃ H₃₂ N₂ O₄.1/2C₄ H₄O₄.1.5H₂ O Requires: C, 70.98; H, 6.04; N, 4.73%.

EXAMPLE 88

Oxalate ofN-[2-methyl-4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.86 g) with2-methyl-4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]benzenamine(Intermediate 16(c) in EP-A-494623) (1.25 g) gave the title compound(0.6 g) as a solid, mp: 230°.

Analysis Found: C, 72.19; H, 6.06; N, 4.54; C₃₄ H₃₄ N₂ O₄.1/2C₂ H₂ O₄Requires: C, 72.51; H, 6.08; N, 4.83%.

EXAMPLE 89

Fumarate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-3-(3-methoxybenzoyl)benzamide

The coupling of Intermediate 14 (0.5 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.63 g) gave, the title compound(0.7 g) as a solid, mp: 188°.

Analysis Found: C, 69.13; H, 6.04; N, 4.13; C₃₆ H₃₈ N₂ O₅.C₄ H₄ O₄Requires: C, 69.15; H, 6.09; N, 4.03%.

EXAMPLE 90

Fumarate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-3-(4-fluorobenzoyl)benzamide

The coupling of Intermediate 15 (0.46 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.64 g) gave, the title compound(0.25 g) as a solid, mp: 176°.

Analysis Found: C, 68.51; H, 5.85; F, 2.86; N, 4.31; C₃₅ H₃₅ FN₂ O₄.C₄H₄ O₄ Requires: C, 68.61; H, 5.76; F, 2.78; N, 4.10%.

EXAMPLE 91

Fumarate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-3-(4-methoxybenzoyl)benzamide

The coupling of 3-(4-methoxybenzoyl)benzoic acid* (0.4 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.53 g) gave the title compound(0.55 g) as a solid, mp: 178°.

Analysis Found: C, 68.85; H, 6.01; N, 4.12; C₃₆ H₃₈ N₂ O₅.C₄ H₄ O₄Requires: C, 69.15; H, 6.09; N, 4.03%.

EXAMPLE 92

Oxalate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-5-(3-fluorobenzoyl)-2-methoxy-benzamide

The coupling of Intermediate 20 (0.5 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.62 g) gave, the title compound(0.6 g) as a solid, mp: 112°.

Analysis Found: C, 66.23; H, 5.73; F, 2.85; N, 4.02; C₃₆ H₃₇ FN₂ O₅.C₂H₂ _(O) ₄ Requires: C, 66.46; H, 5.72; F, 2.77; N, 4.08%.

EXAMPLE 93

Oxalate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-5-benzoyl-2-methoxybenzamide

The coupling of Intermediate 22 (0.5 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.66 g) gave the title compound (1g) as a solid, mp: 202°.

Analysis Found: C, 68.16; H, 6.04; N, 4.13; C₃₆ H₃₈ N₂ O₅.C₂ H₂ _(O) ₄Requires: C, 68.25; H, 6.03; N, 4.19%.

EXAMPLE 94

Oxalate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]5-(3-methoxybenzoyl)-2-methoxybenzamide

The coupling of Intermediate 24 (0.5 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.59 g) gave the title compound (0.8g) as a solid, mp: 116°.

Analysis Found: C, 65.24; H, 6.18; N, 3.81; C₃₇ H₄₀ N₂ O₆. C₂ H₂ O₄.1H₂O Requires: C, 65.35; H, 6.18; N, 3.90%.

EXAMPLE 95

Oxalate ofN-[4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-5-(3-methylbenzoyl)-2-methoxybenzamide

The coupling of 5-(3-methylbenzoyl)-2-methoxybenzoic acid* (0.42 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.53 g) gave the title compound(0.45 g) as a solid, mp: 114°.

Analysis Found: C, 67.56; H, 6.34; N, 3.89; C₃₇ H₄₀ N₂ O₅.C₂ H₂ _(O)₄.1/2H₂ O Requires: C, 67.71; H, 6.26; N, 4.04%.

EXAMPLE 96

Fumarate ofN-[2-methyl-4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (1 g) with Intermediate 11(c) (1.4g) gave the title compound (0.9 g) as a solid, mp=94°.

Analysis Found: C, 65.30; H, 6.16; N, 4.13; C₃₅ H₃₆ N₂ O₅ C₄ H₄ O₄.2H₂ ORequires: C, 65.35; H, 6.18; N, 3.90%.

EXAMPLE 97

N-[4-(4-((4-Fluorobenzyl)methylamino)butyl)phenyl]-9-oxo-4-thioxanthenecarboxamide

The coupling of 9-oxo-4-thioxanthenecarboxylic acid (0.72 g) with4-amino-N-[(4-fluorophenyl)methyl]-N-methylbenzenebutanamine(Intermediate 33(i) in EP-A-494623) (0.86 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.37 g), mp=168°.

Analysis Found: C, 72.54; H, 5.57; F, 3.62; N, 5.92; S, 5.76; C₃₂ H₂₉ F₁N₂ O₂ S₁ Requires: C, 73.26; H, 5.57; F, 3.62; N, 5.34; S, 6.11%.

EXAMPLE 98

N-[2-Methyl-4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (1 g) with Intermediate 11(c)(1.46 g) gave the title compound as an oil (0.86 g), fumarate (fromisopropanol), mp=94°.

Analysis Found: C, 65.30; H, 6.16; N, 4.13; C₃₅ H₃₆ N₂ O₅, C₄ H₄ O₄, 2H₂O Requires: C, 65.34; H, 6.18; N, 3.90%.

EXAMPLE 99

Fumarate ofN-[4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-2-hydroxypropoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.5 g) with Intermediate 13 (0.79g) gave the title compound (0.7 g) as a solid, mp=160°.

Analysis Found: C, 66.92; H, 5.57; N, 4.05; C₃₄ H₃₄ N₂ O₆ C₄ H₄ O₄Requires: C, 66.85; H, 5.61; N, 4.10%.

EXAMPLE 100

Fumarate ofN-[4-[3-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-2-hydroxypropoxy]phenyl]-3-(4-fluorobenzoyl)benzamide

The coupling of Intermediate 15 (0.36 g) with Intermediate 13 (0.44 g)gave the title compound (0.2 g) as a solid, mp=162°-164°.

Analysis Found: C, 65.15; H, 5.41; F, 2.65; N, 4.05; C₃₄ H₃₃ FN₂ O₆ C₄H₄ O₄ Requires: C, 65.14; H, 5.32; F, 2.71; N, 4.00%.

EXAMPLE 101

Oxalate of N-[4-[3-(methylbenzylamino)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.7 g) with Intermediate 11(e)(0.83 g) gave the title compound (1.1 g) as a solid, mp=172°.

Analysis Found: C, 69.92; H, 5.69; N, 4.94; C₃₁ H₃₀ N₂ O₃ C₂ H₂ O₄Requires: C, 69.71; H, 5.67; N, 4.93%.

EXAMPLE 102

Oxalate ofN-[4-[3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propoxy]phenyl]-3-benzoylbenzamide

The coupling of 3-benzoylbenzoic acid (0.4 g) with4-[3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propoxy]benzenamine(Intermediate 88 in EP-A-494623) (0.5 g) gave the title compound (0.37g) as a solid, mp=180°.

Analysis Found: C, 70.21; H, 5.57; N, 4.88; C₃₂ H₃₀ N₂ O₃ C₂ H₂ O₄Requires: C, 70.33; H, 5.56; N, 4.82%.

EXAMPLE 103

N-[4-(2-(Benzylmethylamino)ethoxy)phenyl]-3-benzoylbenamide

The coupling of 3-benzoylbenzoic acid (0.8 g) with Intermediate 19 (0.9g) gave the title compound as an oil (1.1 g), hydrochloride (fromdiethyl ether), mp=140°.

Analysis Found: C, 71.35; H, 5.85; Cl, 6.91; N, 5.43; C₃₀ H₂₇ N₂ O₃, HClRequires: C, 71.92; H, 5.83; Cl, 7.08;

EXAMPLE 104

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide

A mixture of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid* (1 g) and1-hydroxybenzotriazole (0.58 g) in DMF (50 ml) was stirred at roomtemperature for 10 min.4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(intermediate 2(d) in EP-A-494623) (1.1 g) was then added, followed bydicyclohexylcarbodiimide (0.67 g) and the mixture was stirred at roomtemperature for 16 h and then filtered. The filtrate was concentrated invacuo, treated with dilute sodium hydroxide solution and extracted withmethylene chloride. The combined, dried, organic extracts wereevaporated and the residue was purified by column chromatography onsilica gel eluting with methylene chloride/methanol (99:1) to give thetitle compound (0.6 g) as a white solid, after crystallisation fromethyl acetate, mp=117°-120°.

Analysis Found: C, 74.40; H, 6.22; N, 4.63; O, 14.49; C₃₇ H₃₆ N₂ O₅0.5H₂ O Requires: C, 74.35; H, 6.24; N, 4.68; O, 14.72%

The following compounds were prepared in a similar manner:

EXAMPLE 105

N-[4-(3-(Methylveratrylamino)propylthiolphenyl]-1,4-dihydro-4-oxo-3-phenyl-8-quinolinecarboxamide

The coupling of 1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxylic acid*(0.68 g) withN-[3-[(4-aminophenyl)thio]propyl]-3,4-dimethoxy-N-methylbenzenemethanamine(intermediate 38(d) in EP-A-494623) (0.88 g) gave, after crystallisationfrom isopropanol, the title compound as a solid (0.1 g), mp=130°.

Analysis Found: C, 70.89; H, 6.08; N, 6.98; S, 5.50; C₃₅ H₃₅ N₃ O₄ S₁Requires: C, 70.80; H, 5.94; N, 7.08; S, 5.40%.

EXAMPLE 106

N-[4-(3-(Methylveratrylamino)propyl)phenyl]-1.4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxamide

The coupling of 1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxylic acid(0.89 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenepropanamine(Intermediate 33(f) in EP-A-494623) (0.9 g) gave, after crystallisationfrom isopropanol, the title compound as a solid (0.47 g), mp=180°.

Analysis Found: C₇₄.73 ; H, 6.28; N, 7.39; C₃₅ H₃₅ N₃ O₄ Requires: C,74.84; H, 6.28; N, 7.48%.

EXAMPLE 107

N-[4-(2-(Methylveratrylamino)ethoxy)phenyl]-1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxamide

The coupling of 1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxylic acid(0.8 g) withN-[2-(4-aminophenoxy)ethyl]-3,4-dimethoxy-N-methylbenzenemethanamine(Intermediate 36(b) in EP-A-494623) (0.95 g) gave, after crystallisationfrom ethanol, the title compound as a solid (0.6 g), mp=175°.

Analysis Found: C, 72.50; H, 5.82; N, 7.45; C₃₄ H₃₃ N₃ O₅ Requires: C,72.45; H, 5.90; N, 7.45%.

EXAMPLE 108

N-[4-(4-(Methylveratrylamino)butyl)phenyl]-1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxamide

The coupling of 1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxylic acid(0.8 g) with4-amino-N-[(3,4-dimethoxyphenyl)methyl]-N-methylbenzenebutanamine(Intermediate 33(a) in EP-A-494623) (0.52 g) gave, after crystallisationfrom diisopropyl ether, the title compound as a solid (0.13 g), mp=171°.

Analysis Found: C, 72.11; H, 6.59; N, 6.89; C₃₆ H₃₇ N₃ O₄, H₂ ORequires: C, 72.76; H, 6.57; N, 7.06%.

EXAMPLE 109

N-[4-[2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide

The coupling of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid (0.5 g)with4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]benzenamine(Intermediate 2(c) in EP-A-494623) (0.58 g) gave, after crystallisationfrom acetonitrile, the title compound (0.3 g) as a solid, mp 135°-140°.

Analysis Found: C, 73.17; H, 5.78; N, 4.87; O, 16.38; C₃₅ H₃₂ N₂ O₅0.75H₂ O Requires: C, 73.21; H, 5.88; N, 4.85; O, 16.02%.

EXAMPLE 110

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-2-(3-methoxyphenyl)-4-oxo-4H-1-benzopyran-8-carboxamide

The coupling of 2-(3-methoxyphenyl)4-oxo-4H-1-benzopyran-8-carboxylicacid (0.5 g) with 4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinylbutyl]benzenamine (Intermediate 2(d) in EP-A-494623) (0.52 g) gave,after crystallisation from ethyl acetate, the title compound (0.45 g) asa solid, mp=152°.

Analysis Found: C, 73.22; H, 6.21; N, 4.44; O, 16.09; C₃₈ H₃₈ N₂ O₆0.25H₂ O Requires: C, 73.23; H, 6.22; N, 4.49; O, 16.04%.

EXAMPLE 111

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxamide

The coupling of 1,4-dihydro-4-oxo-2-phenyl-8-quinolinecarboxylic acid(0.4 g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.47 g) gave, after crystallisationfrom isopropanol, the title compound (100 mg) as a solid, mp=204°.

Analysis Found: C, 75.01; H, 6.31; N, 7.01; O, 11.60; C₃₇ H₃₇ N₃ O₄0.25H₂ O Requires: C, 75.04; H, 6.38; N, 7.09; O, 11.48%.

EXAMPLE 112

N-[4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]phenyl]-1,4-dihydro-2-(3-methoxyphenyl)-4-oxo-8-quinolinecarboxamide

The coupling of1,4-dihydro-2-(3-methoxyphenyl)-4-oxo-8-quinolinecarboxylic acid (0.22g) with4-[4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine(Intermediate 2(d) in EP-A-494623) (0.25 g) gave, after crystallisationfrom ethyl acetate, the title compound (50 mg) as a solid, mp=116°.

Analysis Found: C, 71.32; H, 6.45; N, 6.63; C₃₈ H₃₉ N₃ O₅ 1.25H₂ ORequires: C, 71.28; H, 6.53; N, 6.56%.

EXAMPLE 113

In vitro cytotoxicity of MDR inhibitors in Chinese Hamster Ovary cells

The multidrug resistant Chinese Hamster Ovary (CHO) cell line CH^(R) C5was obtained from Dr V Ling, Princess Margaret Hospital, Toronto, Canadaand maintained as anchorage-dependent monolayers in α-minimum essentialmedium supplemented with thymidine, adenosine, 10% fetal bovine serum, 2mM L-glutamine (Flow), 100 units/ml penicillin and 100 μg/mlstreptomycin in a humidified atmosphere of 95% air and 5% carbondioxide: Cells were passaged into culture flasks twice a week afterdissociation with EDTA.

CH^(R) C5 cells were seeded at a density of 10⁴ cells/well in microtitreplates. After 24 hours, the medium was removed and replaced by 0.1 ml offresh medium containing successive two-fold dilutions of MDR inhibitors.Each MDR inhibitor was assayed in duplicate in two-fold dilution from1250 to 20 nM. The last well of each column was utilised to verify thelack of toxicity at the top dose of the MDR inhibitor in the absence ofdoxorubicin. Other control conditions were assayed on each microtitreplate: cells alone (1 well), doxorubicin alone (7 wells), amiodarone (arange of two-fold dilutions starting at 5 μM; two wells each). 0.1 ml ofa 10 μg/ml solution of doxorubicin was added. After 72 hours incubationcell viability was assessed by the reduction of3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT;Sigma) to a dark blue formazan product. In particular, 20 μl of a 5mg/ml solution of MTT prepared in phosphate buffered saline was added toeach well. After 4 hours incubation at 37°, the medium was aspirated andreplaced with 0.1 ml dimethylsulphoxide. After vigorous shaking, thequantity of formazan product formed was assessed by its optical densityat 550 nm. The absorbance is directly related to the number of survivingcells in the wells.

Cytotoxicity calculations were performed on the average of the two wellsfor each condition. The concentration of each MDR inhibitor giving a 50%reduction of the optical density relative to cells treated withdoxorubicin alone was determined to give an EC₅₀ value.

Results

In the above test the compounds of the specific Examples hereinabove hadEC₅₀ values of less than 1 μM and are therefore more potent thanprototype MDR inhibitors including amiodarone (EC₅₀ 3 μM) and verapamil(3 μM).

The following are examples of pharmaceutical compositions according tothe invention. The term `Active Ingredient` as used hereinafter means acompound of the invention and may be for example a compound of Examples1-112.

EXAMPLE A

Oral Tablet

    ______________________________________                                                        Per Tablet (mg)                                               ______________________________________                                        Active Ingredient 50.0                                                        Microcrystalline Cellulose                                                                      110.0                                                       Lactose           67.5                                                        Sodium Starch Glycolate                                                                         20.0                                                        Magnesium Stearate                                                                              2.5                                                         Total             250.0                                                       ______________________________________                                    

The drug is sieved through a 250 μm sieve and then the five powders areintimately mixed in a blender and compressed on 3/8 inch standardconcave punches in a tabletting machine.

EXAMPLE B

Oral Capsule

    ______________________________________                                                        Per Capsule (mg)                                              ______________________________________                                        Active Ingredient 50.0                                                        Microcrystalline Cellulose                                                                      66.5                                                        Lactose USP       66.5                                                        Sodium Starch Glycolate                                                                         15.0                                                        Magnesium Stearate                                                                              2.0                                                         Total             200.0                                                       ______________________________________                                    

The drug is sieved through a 250 μm sieve and then the five powders areintimately mixed in a blender and filled into No. 2 hard gelatin capsuleshells on a capsule filling machine.

EXAMPLE C

Injection for Intravenous Administration (10 mg in 10 mL)

    ______________________________________                                                             % w/w                                                    ______________________________________                                        Active Ingredient      0.1                                                    Cancer chemotherapy agent                                                                            as required                                            Water for Injection to 100.0                                                  Dilute hydrochloric acid to                                                                          pH 3.0                                                 ______________________________________                                    

The active ingredient (and cancer chemotherapy agent where appropriate)is dissolved with mixing in the Water For Injection, adding acid slowlyuntil the pH is 3.0. The solution is sparged with nitrogen andfiltratively sterilized through a sterilized filter of 0.22 micron poresize. Under aseptic conditions this sterile solution is placed intosterile ampoules and the ampoules flame sealed.

EXAMPLE D

Oral Syrup

    ______________________________________                                                             % w/v                                                    ______________________________________                                        Active Ingredient      2.0                                                    Cancer chemotherapy agent                                                                            as required                                            Dilute hydrochloric acid to                                                                          pH 3.0                                                 Sobitol solution       60 v/v                                                 Flavour                as required                                            Distilled water to     100                                                    ______________________________________                                    

The active ingredient (and cancer chemotherapy agent where appropriate)is dissolved in some of the water with stirring by adding gradually thehydrochloric acid until the pH is 3.0. The sorbitol solution, flavourand the rest of the water are added and the pH re-adjusted to 3.0. Thesyrup is clarified by filtration through suitable filter pads.

We claim:
 1. A compound of formula (Ia) ##STR13## wherein Z represents ##STR14## X represents an oxygen atom or NH; A represents an oxygen or a sulphur atom, a bond or a group (CH₂)₁ NR⁷ where I represents zero or 1 and R⁷ represents a hydrogen atom or a methyl group;B represents a C₁₋₄ alkylene chain optionally substituted by a hydroxyl group, except that the hydroxyl group and moiety A cannot be attached to the same carbon atom when A represents an oxygen or sulphur atom or a group (CH₂)₁ NR⁷, or when A represents a bond B may also represent a C₂₋₄ alkenylene chain; R² represents a hydrogen or a halogen atom, or a C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylthio group; R³ represents a hydrogen atom or a C₁₋₄ alkoxy group; R⁸ represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ akylthio or nitro group; R⁹ represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylthio group; R¹⁰ and R¹¹ each represent a hydrogen atom or together form a bond or a linking atom selected from --O--, --S-- and NH; and physiologically acceptable salts and solvates thereof.
 2. A compound according to claim 1 in which R⁸ represents a hydrogen or fluorine atom or a C₁₋₄ alkoxy or a C₁₋₄ alkyl group and R⁹ represents a hydrogen atom.
 3. A pharmaceutical composition according to claim 1 in a form suitable for oral, buccal, parenteral or rectal administration.
 4. A pharmaceutical composition according to claim 3 in unit dosage form.
 5. A compound according to claim 1 in which R² and R³ each represent a C₁₋₄ alkoxy group and R⁶ represents a hydrogen atom.
 6. A compound of formula (Ia) ##STR15## wherein Z is as defined in claim 1 above; A represents an oxygen or a sulphur atom or a bond;B represents an unsubstituted C₁₋₄ alkylene chain; R² and R³ each independently represents a C₁₋₄ alkoxy group; and physiologically acceptable salts and solvates thereof.
 7. A compound according to claim 6 in which Z represents ##STR16## wherein R⁸ represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio or nitro group, R⁹ represents a hydrogen or halogen atom or a C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylthio group and X represents an oxygen atom or NH.
 8. A pharmaceutical composition which comprises an effective amount of a compound according to claim 1 together with one or more physiologically acceptable carriers or excipients.
 9. A pharmaceutical composition according to claim 8 in a form suitable for oral, buccal, parenteral or rectal administration.
 10. A pharmaceutical composition according to claim 8 in unit dosage form.
 11. A pharmaceutical composition according to claim 3 in a form suitable for oral administration. 